Heteroaromatic compounds as btk inhibitors

ABSTRACT

The present invention encompasses compounds of the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1 , Cy and Y are defined herein, which are suitable for the treatment of diseases related to BTK, and processes for making these compounds, pharmaceutical preparations containing these compounds, and their methods of use.

TECHNICAL FIELD

The present invention relates to novel compounds which inhibit BTK andtheir use as medicaments.

BACKGROUND INFORMATION

Members of the protein kinase family of human enzymes play importantregulatory roles in a multitude of distinct signal transductionprocesses due to their post-translational modification of specificproteins via the addition of a phosphate group (Hunter, Cell 1987, 50,823-829). Bruton's tyrosine kinase (BTK) is a member of the Tec familyof tyrosine kinases and plays a critical role in B cell development,activation and antibody production.

The contribution of BTK to B cell biology is exemplified in the X-linkedagammaglobulinemia (XLA) immunodeficiency in humans (reviewed inLindvall, Immunol. Rev. 2005, 203, 200-215) that display attenuatedcalcium signaling upon B cell receptor (BCR) engagement, lack mature Bcells in the periphery due to block between pro- and pre-B cell stageand have lower levels of circulating antibodies than normal healthysubjects. The outcome of recent clinical trials with B cell depletinganti-CD20 molecules in diseases such as rheumatoid arthritis (RA) andmultiple sclerosis (MS) support the hypothesis that B cells offer animportant intervention node for controlling autoimmune disorders(Townsend, Immunol. Rev. 2010, 237, 264-283). As such, attenuation of Bcell activation and proliferation via inhibition of BTK may offersimilar therapeutic benefit and is consistent with the demonstratedresistance of BTK-deficient mice to collagen induced arthritis (Jansson,Clin. Exp. Immunol. 1993, 94, 459-465) and experimental autoimmuneencephalitis (Svensson, Eur. J. Immunol. 2002, 32, 1939-1946 and Mangla,Blood 2004, 104, 1191-1197). Similarly, the clinical efficacy observedwith a neutralizing antibody to the B cell stimulating factor BlySsupports a role for B cells in the pathophysiology of systemic lupuserythematosus (SLE) (La Cava, Expert Opin. Biol. Ther. 2010, 10,1555-1561). Given the necessity for BTK for the production ofautoantibodies, including anti-DNA antibodies, in murine models of SLE(Steinberg, J. Clin. Invest. 1982, 70, 587-597; Golding, J. Immunol.1983, 130, 1043-1046; Scribner, J. Immunol. 1987, 138, 3611-3617;Seldin, J. Exp. Med. 1987, 166, 1585-1590; Takeshita, Int. Immunol.1998, 10, 435-4444; Whyburn, J. Immunol. 2003, 171, 1850-1858), BTKinhibitors may offer therapeutic benefit to SLE patients.

Within myeloid cells, BTK signal transduction is necessary for thestimulated release of inflammatory cytokines such as TNFα fromstimulated monocytes (Horwood, J. Exp. Med. 2003, 197, 1603-1611) andfor optimal actin cytoskeletal organization and lacunar bone resorptionin isolated osteoclasts (Danks, J. Bone Miner. Res. 2010, 26, 182-192).Bone marrow derived mast cells lacking BTK exhibit impairedactivation-induced degranulation and cytokine release. Given the role ofBTK in signal transduction processes across multiple cell typesimplicated in the pathogenesis of autoimmune and allergic disorders,inhibition of BTK activity may provide clinical benefit in diseases suchas RA, MS, SLE, lupus nephritis, Sjogren's disease, vasculitis, asthmaand allergic disorders.

SUMMARY OF THE INVENTION

Currently, compounds such as A and C (discussed below), and thosedepicted in, for example, PCT publication number WO2014025976 are knownas BTK inhibitors. However, as provided herein below, these compoundscross-react with and inhibit other kinases. Hence, these representativesare not selective for BTK over other targets. The lack of selective BTKinhibition increases the likelihood of adverse effects in a clinicalsetting.

Beside efficacy and selectivity, a therapeutic compound must have afavorable safety profile such as cardiovascular safety. One parameterfor assessing the cardiovascular (CV) safety of a compound is the meanarterial pressure (MAP). A statistically significant change in MAP in apre-clinical rat CV safety study is indicative of adverse cardiovascularevents in human. As provided herein below, comparative compounds A, B,and C show statistically significant increases in MAP in a rat CV study.The data suggests that these compounds may not have a favorablecardiovascular safety profile in human.

In view of the above-mentioned safety concerns with the other known BTKinhibitors, there still remains a need for additional compounds that arehighly selective for BTK inhibition and do not have an adverse impact onrelevant cardiovascular parameters such as MAP.

The compounds of the present invention maintain the requisite potentinhibitory activity against BTK to treat the aforementioned BTK-relateddiseases, and solve the selectivity and cardiovascular safety problemsassociated with other known BTK inhibitors such as those represented bycomparative compounds A, B, and C (discussed below). The BTK selectivityand the favorable cardiovascular safety profile that are demonstrated bythe compounds of the instant invention represent unexpected andsurprising improvements over other known BTK inhibitors.

In particular, the compounds of the present invention solve the efficacyand safety problems associated with other known BTK inhibitors bymaintaining a high level of potency and selectivity in inhibiting theBTK activity without having any statistically significant effects onMAP.

Accordingly, this invention comprises a novel class of heteroaromaticcompounds and methods for making and using the same. These compounds areuseful for the treatment of autoimmune and allergic disorders in thatthey exhibit excellent inhibitory effect upon BTK.

In a first generic embodiment, there is provided a compound of theformula (I)

in which:Cy is chosen from

each R₁ is independently chosen from hydrogen or methyl;R₂ is L-Ar, wherein Ar is phenyl or pyridinyl and each is optionallysubstituted by one or more of halogen, halo C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄alkoxy, —CN, halo C₁₋₄ alkoxy, or cycloalkyl;L is —(CH₂)— or —(CHCH₃)—;Y is C₆-C₈ spirocycle containing 1 ring nitrogen atom, and issubstituted by one R₃;R₃ is chosen from

each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, or C₃₋₄cycloalkyl;each group defined above for R₁-R₄ and Y can be where possible partiallyor fully halogenated;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiment herein-above and in which:

Y is chosen from

or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiments herein-above and in which:

Cy is

Y is chosen from

R₃ is

in which each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, orC₃₋₄ cycloalkyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiment herein-above and in which:

Y is chosen from

R₃ is

in which R₄ is chosen from hydrogen, C₁₋₄ alkyl, or C₃₋₄ cycloalkyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiment herein-above and in which:

Cy is

Y is chosen from

R₃ is

in which R₄ is chosen from hydrogen, C₁₋₄ alkyl, or C₃₋₄ cycloalkyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiment herein-above and in which:

Cy is

Y is chosen from

R₃ is

in which each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, orC₃₋₄ cycloalkyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to the embodiment herein-above and in which:

Cy is

Y is chosen from

R₃ is

in which each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, orC₃₋₄ cycloalkyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to any of the embodiments herein-above and in which:

each R₄ is independently chosen from hydrogen, methyl, or cyclopropyl;or a pharmaceutically acceptable salt or hydrate thereof.

In a further embodiment, there is provided a compound of the formula (I)according to any of the embodiments herein-above and in which:

R₂ is L-Ar, wherein Ar is phenyl or pyridinyl and each is optionallysubstituted by one or more of halogen, halomethyl, methyl, methoxy, —CN,halomethoxy, or cyclopropyl;L is —(CH₂)— or —(CHCH₃)—or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the invention provides made compounds in Table Iwhich can be made in view of the general schemes, examples and methodsdescribed herein and those known in the art.

TABLE I Biological and physical properties of representatives of thepresent invention BTK IC₅₀ HPLC RT m/z Example Structure (nM) Method(min) [M + H]⁺ 1

36 A 0.65 446.4 2

0.3 B 0.596 491.1 3

0.4 B 0.797 559.1 4

1.8 B 0.795 540.3 5

0.4 B 0.808 540.3 6

0.4 B 0.813 540.3 7

3.3 B 0.778 555.2 8

0.9 B 0.80 559.1 9

0.6 A 0.80 542.3 10

0.5 B 0.751 551.3 11

0.7 B 0.647 483.3 12

0.5 B 0.770 526.4 13

9.1 B 0.665 527.2 14

0.5 B 0.7 527.2 15

1.1 B 0.814 540.3 16

1.5 B 0.595 472.5 17

1.7 B 0.798 539.2 18

0.6 B 0.798 539.2 19

0.9 B 0.777 540.3 20

22 B 0.741 528.7 21

5.8 B 0.786 554.3 22

0.3 B 0.760 526.3 23

1.3 B 0.796 540.3 24

0.8 B 0.801 512.4 25

2.6 B 0.843 526.3 26

2.6 C 1.78 532.4 27

1.7 B 0.769 506.3 28

0.3 B 0.692 476.4 29

0.8 B 0.69 476.4 30

0.6 B 0.786 544.4 31

0.8 B 0.779 544.3 32

0.5 B 0.772 544.4 33

0.4 B 0.78 544.2 34

0.7 B 0.753 506.2 35

0.9 B 0.724 522.3 36

0.2 B 0.716 508.3 37

0.8 B 0.788 512.3 38

3.0 A 0.87 540.2 39

0.9 B 0.758 560.3 40

4.2 B 0.722 472.4 41

0.3 B 0.734 484.3 42

78 B 0.716 514.4 43

3.0 B 0.722 486.4 44

0.3 B 0.672 458.3 45

6.0 A 0.64 444.3 46

7.9 B 0.761 526.3 47

0.5 A 0.78 512.3 48

16 A 0.59 432.3 49

45 B 0.802 580.3 50

63 B 0.728 511.1 51

0.3 B 0.766 498.4 52

1.2 B 0.7345 486.4 53

0.3 B 0.743 510.3 54

0.5 B 0.73 492.2 55

0.7 B 0.84 510.3 56

0.6 B 0.775 544.3 57

0.9 B 0.778 544.3 58

0.4 B 0.809 559.1 59

0.3 B 0.707 494.2 60

0.5 B 0.688 476.3

In a second generic embodiment, there is provided a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to the first embodiment or any of its related embodiments or apharmaceutically acceptable salt thereof.

In a third generic embodiment, there is provided a method of treating adisease chosen from rheumatoid arthritis, systemic lupus erythromatosis,lupus nephritis, Sjogren's disease, vasculitis, scleroderma, asthma,allergic rhinitis, allergic eczema, B cell lymphoma, multiple sclerosis,juvenile rheumatoid arthritis, juvenile idiopathic arthritis,inflammatory bowel disease, graft versus host disease, psoriaticarthritis, ankylosing spondylitis and uveitis, comprising administeringto a patient a therapeutically effective amount of a compound accordingto the first embodiment or any of its related embodiments or apharmaceutically acceptable salt thereof.

In a forth generic embodiment, there is provided a process forpreparation of a compound according to the first embodiment or any ofits related embodiments by:

(i) coupling a compound of formula A

with a compound of formula E

to form a compound of formula G

wherein each R₁ is independently chosen from hydrogen or methyl; X is ahalogen (i.e. chloro, bromo, or iodo); LG is a leaving group; and Y′ isC₆-C₈ spirocycle containing 1 ring nitrogen capped by a protectinggroup;(ii) coupling the compound of formula (I-1) with a heterocyclic boronicester or acid of formula C

in presence of a suitable base and palladium catalyst followed byhydrolysis of the nitrile to carboxamide to form a compound of formula(II-1)

wherein each R group of the compound of formula C is H, alkyl, or both Rgroups are connected to form a ring;Cy in the compound of formula (II-1) is chosen from

R₂ is L-Ar, wherein Ar is phenyl or pyridinyl and each is optionallysubstituted by one or more of halogen, halo C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄alkoxy, —CN, halo C₁₋₄ alkoxy, or cycloalkyl;L is —(CH₂)— or —(CHCH₃)—; and(iii) Deprotecting the capped nitrogen of the compound of formula (II-1)under an acidic condition and coupling the deprotected compound offormula (II-1) with a compound chosen from

to form a compound of formula (I)

wherein Y is C₆-C₈ spirocycle containing 1 ring nitrogen bonded orcovalently linked to R₃, wherein

R₃ is

each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, or C₃₋₄cycloalkyl;or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawing, which is included to provide furtherunderstanding of the subject technology and is incorporated in andconstitute a part of this specification, illustrates aspects of thesubject technology and together with the description serves to explainthe principles of the subject technology.

FIG. 1 shows that the compounds of the present invention, e.g., Examples12 and 22, elicit no effect on mean arterial pressure (MAP) in-vivo incomparison to the comparative compounds A-C (described in the examplesection).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Terms that are not specifically defined here have the meanings that areapparent to the skilled man in the light of the overall disclosure andthe context as a whole.

As used herein, the following definitions apply, unless statedotherwise: The use of the prefix C_(x-y), wherein x and y each representa natural number, indicates that the chain or ring structure orcombination of chain and ring structure as a whole, specified andmentioned in direct association, may consist of a maximum of y and aminimum of x carbon atoms.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both straight-chain (unbranched) and branched form. If analkyl is substituted, the substitution may take place independently ofone another, by mono- or polysubstitution in each case, on all thehydrogen-carrying carbon atoms.

For example, the term “C₁₋₅ alkyl” includes for example H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃),1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl;—CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu;—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl(—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃),3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl(—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃),1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl,1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, wherein allisomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother (combined) group such as for example C_(x-y) alkylamino orC_(x-y) alkoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C double bondand a carbon atom can only be part of one C—C double bond. If in analkyl as hereinbefore defined having at least two carbon atoms, twohydrogen atoms on adjacent carbon atoms are formally removed and thefree valencies are saturated to form a second bond, the correspondingalkenyl is formed.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCl═CH₂, —CBr═CH₂, —C≡C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems aresaturated. In bicyclic hydrocarbon rings two rings are joined togetherso that they have at least two carbon atoms together.

If a cycloalkyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl.

Corresponding groups are an example:

Spirocycle is a spiro-hydrocarbon ring one carbon atom (spiroatom)belongs to two rings together.

Aryl denotes mono-, bi- or tricyclic carbocycles with at least onearomatic carbocycle. Preferably, it denotes a monocyclic group with sixcarbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms(two six-membered rings or one six-membered ring with a five-memberedring), wherein the second ring may also be aromatic or, however, mayalso be saturated or partially saturated.

If an aryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Aryl itself maybe linked as a substituent to the molecule via every suitable positionof the ring system.

Examples of aryl are phenyl and naphthyl.

The above definition of aryl also applies if aryl is part of another(combined) group as for example in arylamino, aryloxy or arylalkyl.

Heterocyclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl or spirocycle by replacing one or more of the groups—CH₂— independently of one another in the hydrocarbon rings by thegroups —O—, —S— or —NH—, wherein a total of not more than fiveheteroatoms may be present, at least one carbon atom may be presentbetween two oxygen atoms and between two sulphur atoms or between oneoxygen and one sulphur atom and the ring as a whole must have chemicalstability. Heteroatoms may optionally be present in all the possibleoxidation stages (sulphur→sulphoxide —SO—, sulphone —SO₂—;nitrogen→N-oxide).

If a heterocyclyl is substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heterocyclyl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system.

Examples of heterocyclyl are tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,

or the following heterocyclic spirocycles

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl, instead of one or more carbon atoms,one or more identical or different heteroatoms, selected independentlyof one another from among nitrogen, sulphur and oxygen, wherein theresulting group must be chemically stable. The prerequisite for thepresence of heteroaryl is a heteroatom and a heteroaromatic system.

If a heteroaryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heteroaryl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system, both carbon and nitrogen.

Examples of heteroaryl are pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl,benzimidazolyl, benzothiazolyl, and the like.

Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide).

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic either aromaticor non-aromatic ring systems. The non-aromatic ring systems may be mono-or polyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl.

All cyclic and acyclic systems defined in this section hereinabove shallbe understood to be optionally partially or fully halogenated wherepossible and unless otherwise indicated.

Stereochemistry/Solvates/Hydrates:

Unless specifically indicated, throughout the specification and appendedclaims, a given chemical formula or name shall encompass tautomers andall stereo, optical and geometrical isomers (e.g. enantiomers,diastereomers, E/Z isomers, etc.) and racemates thereof as well asmixtures in different proportions of the separate enantiomers, mixturesof diastereomers, or mixtures of any of the foregoing forms where suchisomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof. The compounds and salts ofthe invention can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol and thelike. In general, the solvated forms such as hydrates are consideredequivalent to the unsolvated forms for the purposes of the invention.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²p,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

For example, such salts include acetates, ascorbates,benzenesulphonates, benzoates, besylates, bicarbonates, bitartrates,bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates,chlorides/hydrochlorides, citrates, edisylates, ethane disulphonates,estolates esylates, fumarates, gluceptates, gluconates, glutamates,glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines,hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates,lactobionates, malates, maleates, mandelates, methanesulphonates,mesylates, methylbromides, methylnitrates, methylsulphates, mucates,napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates,salicylates, stearates, subacetates, succinates, sulphamides, sulphates,tannates, tartrates, teoclates, toluenesulphonates, triethiodides,ammonium, benzathines, chloroprocaines, cholines, diethanolamines,ethylenediamines, meglumines and procaines.

Further pharmaceutically acceptable salts can be formed with cationsfrom metals like aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and the like (also see Pharmaceutical salts, Birge, S. M.et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesised from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base form of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoroacetates), also comprise a part of the invention.

Some abbreviated notations and their structure correspondences arelisted below:

In a representation such as for example

the solid line means that the ring system may be attached to themolecule via the carbon atom 1, 2 or 3, and is thus equivalent to thefollowing representation

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or alleviating these symptoms, or which prolong the survivalof a treated patient.

List of abbreviations Ac Acetyl ACN Acetonitrile aq Aqueous Ar Argon ATPadenosine triphosphate Bn Benzyl Bu Butyl Boc tert-butyloxycarbonyl catCatalyst conc concentrated d day(s) DCM Dichloromethane DIPEAN,N-diisopropylethylamine DMAP 4-N,N-dimethylaminopyridine DMADimethylacetamide DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSODimethylsulphoxide dppf 1.1′-bis(diphenylphosphino)ferrocene EDC1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI electron sprayionization Et Ethyl Et₂O diethyl ether EtOAc ethyl acetate EtOH Ethanolh hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate Hep Heptane HPLC high performance liquidchromatography i Iso IPAc Isopropyl acetate LC liquid chromatographyLiHMDS lithium bis(trimethylsilyl)amide sln. Solution mCPBA3-Chloroperoxbenzoic acid Me Methyl MeOH Methanol min Minutes MPLCmedium pressure liquid chromatography MS mass spectrometry m/zmass-to-charge ratio NBS N-bromo-succinimide NIS N-iodo-succinimide NMMN-methylmorpholine NMP N-methylpyrrolidone NP normal phase n.a. notavailable PBS phosphate-buffered saline Ph Phenyl Pr Propyl Pyr Pyridinerac Racemic Rf (R_(f)) retention factor RP reversed phase RT Retentiontime (HPLC) rt ambient temperature TBAF tetrabutylammonium fluorideTBDMS tert-butyldimethylsilyl TBME tert-butylmethylether TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroboratetBu tert-butyl TEA Triethylamine temp. Temperature tert Tertiary TfTriflate TFA trifluoroacetic acid THF Tetrahydrofuran TMS TrimethylsilylTRIS tris(hydroxymethyl)-aminomethane Ts p-Tosyl TsOH p-toluenesulphonicacid UV Ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed examples which illustrate the fundamentalsof the invention by way of example without restricting its scope:

Preparation of the Compounds According to the Invention

General Synthetic Methods

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Intermediates and productsmay be purified by chromatography on silica gel, recrystallizationand/or reverse phase HPLC (RHPLC). Discrete enantiomers may be obtainedby resolution of racemic products using chiral HPLC. RHPLC purificationmethods used anywhere from 0-100% acetonitrile in water containing 0.1%formic acid, 0.1% TFA, or 2.5 mM ammonium bicarbonate and used one ofthe following columns:

a) Waters Sunfire OBD C18 5 μm 30×150 mm columnb) Waters XBridge OBD C18 5 μm 30×150 mm columnc) Waters ODB C8 5 μm 19×150 mm columnd) Waters Atlantis ODB C18 5 μm 19×50 mm columne) Waters Atlantis T3 OBD 5 μm 30×100 mm columnf) Phenomenex Gemini Axia C18 5 μm 30×100 mm column

HPLC Methods:

TABLE 1 Analytical HPLC Method A Mobile Mobile Gradient Phase Phase Time% % Flow Method A B (min) A B (mL/min.) Column A 0.05% 0.05% 0 90.0 10.00.8 CSH C18 Formic Formic 1.19 0 100 2.1 × 50 Acid in Acid in 1.70 0 100mm, 95% ACN 1.7 μm water/ particle 5% diameter ACN

TABLE 2 Analytical HPLC Method B Mobile Mobile Gradient Phase Phase Time% % Flow Method A B (min) A B (mL/min.) Column A 0.1% 0.1% 0 95.0 5.00.8 BEH Formic Formic 1.0 5.0 95.0 2.5 × 50 mm Acid in Acid in 1.3 5.095.0 C18, 1.7 μm Water ACN 1.4 95.0 5.0 particle 1.7 95.0 5.0 diameter

TABLE 3 Analytical HPLC Method C Mobile Mobile Gradient Phase Phase Time% % Flow Method A B (min) A B (mL/min.) Column A 0.05% 0.05% 0 90.0 10.00.8 CSH C18 Formic Formic 4.45 0 100 2.1 × 50 Acid in Acid in 4.58 0 100mm, 95% ACN 1.7 μm water/ particle 5% diameter ACN

The compounds according to the invention are prepared by the methods ofsynthesis described hereinafter in which the substituents of the generalformulae have the meanings given hereinbefore. These methods areintended as an illustration of the invention without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to knowncompounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.

Amide bond formations may be carried out by standard coupling conditionswell-known in the art (e.g., Bodanszky, M. The Practice of PeptideSynthesis, Springer-Verlag, 1984, which is herein incorporated byreference in its entirety), such as reacting a carboxylic acid and anamine in the presence of a coupling reagents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU). Use of protective groups (i.e., protectionor de-protection of a functional group) may be carried out by standardconditions well-known in the art (e.g., Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 3rd Ed. New York, Wiley, 1999,which is herein incorporated by reference in its entirety).

Compounds of formula I may be prepared as shown in Scheme I or II below.

In Scheme I, a pyrazole of formula A, in which X may be bromo, chloro,or iodo, is reacted with a suitable boronic acid of formula B (R═H), asuitable boronic ester of formula B (R=methyl), or a suitable boronicester of formula C under a palladium catalysed cross-coupling conditionsuch as the presence of a suitable base (e.g., aqueous Cs₂CO₃, NaH), asuitable catalyst [e.g., tetrakis(triphenylphosphine)palladium(0)], in asuitable solvent (e.g., DME) and at a suitable temperature to provide acompound of formula D. The heterocycle D is reacted with a compound offormula E, wherein LG is a suitable leaving group (e.g., O-Ts), in asuitable solvent (e.g., DMA), in the presence of a suitable base (e.g.,NaH) and at a suitable temperature to afford a compound of formula F.The nitrile F is hydrolysed to the corresponding carboxamide under asuitable condition such as in a suitable solvent or a mixture ofsolvents (e.g., a mixture of water and ethanol), in the presence of asuitable reagent such as (hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) and at a suitable temperature.The subsequent deprotection and amide coupling using conditionswell-known in the art such as those described above provide a compoundof formula (I).

Additionally, compounds of formula I may be prepared according to SchemeII.

According to Scheme II, a pyrazole of formula A, in which X may bebromo, chloro, or iodo, may be reacted with a compound of formula E,wherein LG is a leaving group (e.g., O-Ts), in a suitable solvent (e.g.,acetone), in the presence of a suitable base such (e.g., Cs₂CO₃, NaH)and at a suitable temperature to afford a heterocycle of formula G. Theamino-pyrazole G may be reacted with a suitable boronic acid of formulaB (R═H), a suitable boronic ester of formula B (R=methyl) or a suitableboronic ester of formula C under a palladium catalysed cross-couplingcondition such as the presence of a suitable base (e.g., aqueous K₂CO₃),a suitable catalyst [e.g., tetrakis(triphenylphosphine)palladium(0)], ina suitable solvent (e.g., DME) and at a suitable temperature to generatea compound of formula F. The nitrile F may be converted to a compound offormula (I) according to the method described in Scheme I.

SYNTHETIC EXAMPLES

Method A

Synthesis of Intermediate I-1

Cs₂CO₃ is added to a solution of the R-1 (22.0 g, 118 mmol) and R-2(47.6 g, 129 mmol) in acetone (250 mL). The mixture is heated at 80° C.for 2 days. The mixture is diluted with water (200 mL) and extractedwith CH₂Cl₂ (100 mL×2). The organics are then collected and concentratedto give I-1 (25 g), m/z=382.1 [M+H].

Method B

Synthesis of Intermediate I-2

Sodium hydride (14.3 g; 372.2 mmol) is added to a solution of the R-1(58 g; 310.2 mmol) in DMA (460 mL). After 30 min, R-3 (130.2 g; 341.2mmol) is added and heated at 80° C. for 18 h. The reaction is cooled toroom temperature and diluted with MeOH (250 mL) and water (35 mL). Thereaction is then stirred vigorously overnight. The heterogeneous mixtureis vacuum filtered to yield, after drying, 96 g of a solid as a 1:1mixture of pyrazole isomers. The solid is combined with 240 mL of CH₂Cl₂and stirred vigorously overnight. The heterogeneous mixture is vacuumfiltered and yielded 40 g of an off white solid. The solid is combinedwith 58 mL of CH₂Cl₂ and stirred vigorously. After 2 h, theheterogeneous solution is sonicated for 5 minutes and then cooled to 5°C. and stirred for 1 h. The heterogeneous solution is vacuum filteredand the solid is washed with cold CH₂Cl₂ (2×), collected and dried toyield I-2 (27.7 g). The combined filtrates are diluted with 180 mL ofi-PrOH and stirred vigorously for 3 h. The heterogeneous solution isfiltered and the solid is washed with a small amount of i-PrOH (2×). Thefiltrate is concentrated in vacuo to give a residue that is combinedwith 32 mL of CH₂Cl₂ and sonicated for 5 minutes. After an additional 1h of stirring, the solution is cooled to 0° C. and stirred 1 h. Theheterogeneous solution is filtered and solid collected and dried toyield additional amounts of I-2 (5.6 g). Total amount of I-2 isolated is33.3 g, m/z 394.0/396.0 [M+H].

Method C

Synthesis of Intermediate I-3

I-I (1.1 g, 2.9 mmol), R-4 (1.71 g, 3.2 mmol), 2M aqueous potassiumcarbonate (2.9 ml, 5.8 mmol), tetrakis(triphenylphosphine)palladium(0)(333 mg, 0.3 mmol) and DME (6 mL) are combined and sealed in a microwavetube and heated to 120° C. thermally overnight. The mixture is filtered,then diluted with water (100 mL) and extracted with EtOAc (4×200 mL).The combined EtOAc layers are dried over sodium sulfate andconcentrated. The crude residue is purified by flash chromatography(SiO₂, 0-60% EtOAc/Heptane) to yield 1.2 g of I-3, m/z=500.5 [M+H].

The following intermediate is prepared in similar fashion:

Structure Intermediate m/z

I-4 460.7 [M + H]

Method D

Synthesis of Intermediate I-5

R-1 (2.0 g, 10.7 mmol), R-4 (6.4 g, 60%, 11.8 mmol), 2M aqueous Cs₂CO₃(10.7 ml; 21 mmol), tetrakis(triphenylphosphine)palladium(0) (1.2 g; 1.1mmol), and DME (6 mL) are combined in a microwave tube and heated to135° C. in a microwave for 2 hours. The mixture is filtered, thendiluted with water and extracted with EtOAc. The combined extracts aredried over sodium sulfate and concentrated to provide a crude residuethat is purified by flash chromatography (0-100% EtOAc in heptane) toyield 3.2 g of I-5, m/z=382.1 [M+H].

The following intermediates are prepared in similar fashion:

Inter- Structure mediate m/z

I-6 319.1 [M + H]

I-7 265.2 [M + H]

Method E

Synthesis of Intermediate I-8

Sodium hydride (250 mg, 6.5 mmol) is added to a solution of I-5 (1.64 g,5.4 mmol) in DMA (10 mL). After 5 min, R-3 (2.26 g, 5.9 mmol) is addedand heated at 70° C. for 18 h. The mixture is diluted with water (20 mL)and extracted with EtOAc (4×10 mL). The combined EtOAc extracts aredried over sodium sulfate, filtrate and then concentrated in vacuo. Thecrude residue is purified by flash chromatography (SiO₂, 0-50% EtOAc inheptane) to provide 1.1 g of I-8, m/z=514.5 [M+H].

The following intermediate is prepared in similar fashion:

Inter- Structure mediate m/z

I-9 528.3 [M + H]

Method F

Synthesis of Intermediate I-10

I-3 (845 mg, 1.7 mmol) is dissolved in THF (15 mL). A 1M solution of R-5in THF (5.1 ml, 5.1 mmol) is added to the solution. The mixture isstirred at 70° C. overnight. The reaction solution is partitionedbetween saturated NH₄Cl (aq. solution) and EtOAc. The layers areseparated and the organic layer is concentrated in vacuo. A small amountof CH₂Cl₂ is added to the residue and the resulting solid is filtered toyield 900 mg of I-10, m/z=370.3 [M+H].

The following intermediates are prepared in similar fashion:

Structure Intermediate m/z

I-11 384.3 [M + H]

I-12 398.2 [M + H]

Method G

Synthesis of Intermediate I-13

Potassium carbonate (270 mg, 1.94 mmol) is added to a solution of I-10(143 mg, 0.39 mmol) in DMA (5 mL). After 5 min, R-6 (110 mg, 0.47 mmol)is added and the solution is heated to 70° C. for 18 h. The crudesolution is loaded directly onto a silica column and purified (Gradient:0-60% EtOAc in heptane) to yield 71 mg of I-13, m/z=528.4 [M+H].

The following intermediates are prepared in similar fashion:

Structure Intermediate m/z

I-14 328.4 [M + H]

I-15 542.4 [M + H]

I-16 596.4 [M + H]

I-17 542.4 [M + H]

I-18 576.3 [M + H]

I-19 556.4 [M + H]

I-20 556.3 [M + H]

Method H

Synthesis of Intermediate I-21

To a stirred solution of R-7 (19.2 g, 99.1 mmol) in DMA (54 mL) is addedpotassium carbonate (27.4 g, 198.1 mmol). R-8 (23.0 g, 109 mmol) is thenadded slowly. The reaction is stirred at room temperature for 6 h. Thereaction is then quenched with water and extracted with EtOAc. The EtOAcis concentrated in vacuo and residue is purified by flash chromatography(SiO₂, 10% EtOAc in hexanes) to yield 18 g of I-21, m/z=324.4 [M+H].

The following intermediates are prepared in similar fashion:

Inter- Structure mediate m/z

I-22 367.2 [M + H]

I-23 313.6 [M + H]

I-24 337.1/ 339.2 [M + H]

I-25 319.2/ 321.1 [M + H]

I-26 370.1/ 371.9 [M + H]

I-27 370.3 [M + H]

I-28 321.4 [M + H]

I-29 303.4 [M + H]

I-30 286.0 [M + H]

Method I

Synthesis of Intermediate I-31

In a 1 L flask is placed R-7 (25 g, 128.8 mmol) and potassium carbonate(35.6 g, 257.7 mmol) in 100 ml of DMF. To this mixture is added R-9(33.9 g, 141.7 mmol) and the reaction allowed to stir overnight. Thereaction is then filtered and concentrated. The residue is dissolved inCH₂Cl₂ and filtered through Celite. The filtrate is concentrated toprovide 45.4 g of I-31, m/z=353.4 [M+H]. Intermediate I-31 is used insubsequent steps without further purification.

The following intermediates are prepared in similar fashion:

Inter- Structure mediate m/z

I-32 367.1 [M + H]

I-33

I-34

I-35 367.2 [M + H]

I-36 383.1 [M + H]

I-37 387.1 [M + H]

I-38 319.2 [M + H]

I-39 431.1 [M + H]

I-40 369.2 [M + H]

I-41 310.1 [M + H]

I-42 377.7 [M + H]

I-43 300.5 [M + H]

I-44 353.9 [M + H]

I-45 367.3 [M + H]

I-46 354.3 [M + H]

I-47 330.0 [M + H]

I-48 349.4 [M + H]

I-49 353.5 [M + H]

I-50 313.1 [M + H]

I-51 336.1/ 338.1 [M + H]

Method J

Synthesis of Intermediate I-52

In a 1 L flask is placed R-7 (75 g, 386.5 mmol) and K₂CO₃ (106.7 g, 773mmol) in 100 mL DMF. To this is added R-10 (101.6 g, 425.2 mmol) and thereaction allowed to stir overnight. The reaction is filtered andconcentrated. The residue is dissolved in CH₂Cl₂ and filtered throughCelite. The filtrate is concentrated to provide 136 g of I-52, m/z=353.0[M+H]. Intermediate I-52 is used in subsequent steps without furtherpurification.

Method K

Synthesis of Mixture of Intermediates I-53

To a mixture of R-7 (5.0 g, 25.8 mmol), acetonitrile (29 mL) andpotassium carbonate (7.1 g, 51.5 mmol) is added R-11 (3.9 mL, 25.6mmol). The mixture is stirred for 18 h under Ar. The reaction is thenconcentrated and the residue is partitioned between EtOAc and water. Thelayers are separated and the aqueous layer is extracted with EtOAc (2×).The combined organic layers are washed with brine, dried over MgSO₄,filtered and concentrated to yield 8.75 g of I-53, m/z=271.0 [M+H].Intermediate I-53 mixture is used in subsequent steps without furtherpurification.

The following intermediates are prepared in similar fashion:

Inter- me- Structure diate m/z

I-54 289 [M + H]

I-55 289 [M + H]

I-56 289 [M + H]

I-57 289 [M + H]

I-58 221 [M + H]

I-59 221 [M + H]

Method L

Synthesis of Intermediate I-60

I-2 (1.1 g, 2.8 mmol), I-53 (1.12 g, 4.16 mmol), cesium carbonate (1.81g, 5.5 mmol) are combined in a microwave tube and the vessel is flushedwith Ar. DME (6.6 mL) and Pd(PPh₃)₄ (320 mg, 0.28 mmol) are added andthe vessel is degassed and thermally heated to 125° C. overnight. Themixture is filtered through Celite and the Celite is washed with EtOAcand water. The layers are separated and the aqueous is extracted withEtOAc (2×). The combined organic layers are washed with brine, driedover MgSO₄, filtered and concentrated. The residue is purified by flashchromatography (SiO₂, 10-80% EtOAc in heptane) to give 407 mg of I-60,m/z=542.2 [M+H].

Method M

Synthesis of Intermediate I-61

I-2 (1.0 g, 1.31 mmol), I-30 (790 mg, 2.8 mmol), cesium carbonate (1.6g, 5.1 mmol), Pd(PPh₃)₄ (0.29 g, 0.25 mmol) and DME (6 mL) are combinedin a microwave tube and heated thermally to 125° C. overnight. Themixture is filtered, then diluted with water (30 mL) and extracted withEtOAc (4×30 mL). The combined organic extracts are dried over sodiumsulfate, filtered and concentrated to provide the crude residue. Thecrude material is purified via flash chromatography (SiO₂, 0-100% EtOAcin heptane) to yield 1.1 g of I-61, m/z=474.3 [M+H].

The following intermediates are prepared in similar fashion:

Inter- me- Structure diate m/z

I-62 488.5 [M + H]

I-63 508.2/ 510.2 [M + H]

I-64 558.4 [M + H]

I-65 488.4 [M + H]

I-66 492.0 [M + H]

I-67 492.0 [M + H]

I-68 524.3 [M + H]

I-69 542.5 [M + H]

I-70 508.2/ 510.2 [M + H]

I-71 576.3 [M + H]

I-72 576.3 [M + H]

I-73 560.0 [M + H]

I-74 560.0 [M + H]

I-75 560.0 [M + H]

I-76 560.0 [M + H]

I-77 526.2/ 528.2 [M + H]

I-78 526.3/ 528.2 [M + H]

I-79 556.4 [M + H]

I-80 543.3 [M + H]

I-81 543.3 [M + H]

I-82 520.2/ 522.2 [M + H]

I-83 502.3 [M + H]

I-84 528.4 [M + H]

I-85 556.3 [M + H]

I-86 538.4 [M + H]

Method N

Synthesis of Intermediate I-87

I-2 (0.7 g, 1.8 mmol), I-39 (1.5 g, 3.5 mmol), cesium carbonate (1.15 g,3.5 mmol), Pd(PPh₃)₄ (0.2 g, 0.21 mmol), are combined in a microwavetube. Degassed dioxane (8 mL) and water (2 mL) are added. The reactionvessel is sealed under Ar and heated in a microwave for 60 min at 125°C. The reaction is transferred to a separatory funnel, diluted withEtOAc and rinsed with water and brine. The organics are dried, filtered,and evaporated in vacuo. The residue is then purified via flashchromatography (SiO₂, 0-55% EtOAc/heptane) to yield 710 mg of I-87,m/z=622.2 [M+H].

The following intermediates are prepared in similar fashion:

Inter- me- Structure diate m/z

I-88 558.4 [M + H]

I-89

I-90 556.3 [M + H]

I-91 556.3 [M + H]

I-92 556.4 [M + H]

I-93 572.4 [M + H]

I-94 576.3 [M + H]

Method O

Synthesis of Intermediate I-95

I-2 (310 mg, 0.78 mmol), I-21 (380 mg, 1.17 mmol),tricyclohexylphosphine (175 mg, 0.63 mmol) and potassium phosphate (500mg, 2.3 mmol) are combined in 20 mL microwave vial in 8 ml of dioxaneand 2 mL of water. Ar is bubbled through the solution for 10 minutes.Tris(dibenzylideneacetone)dipalladium (0) is then added and Ar isbubbled through the reaction for another 5 minutes. The reaction issealed and heated in a microwave for 60 min at 120° C. After cooling tort, the reaction solution is diluted with water and extracted with EtOAc(2×).

The combined organic extracts are dried over MgSO₄, filtered, andconcentrated in vacuo. The crude reside is purified by flashchromatography (SiO₂, 10-90% EtOAc in heptane) and yields 340 mg ofI-95, m/z=514.3 [M+H].

The following intermediates are prepared in similar fashion:

Inter- me- Structure diate m/z

I-96 492.3 [M + H]

I-97 560.2 [M + H]

I-98 560.0 [M + H]

I-99 510.3 [M + H]

I-100 571.7 [M + H]

Method P

Synthesis of Intermediate I-101

In a 1 L flask is placed I-2 (32.0 g, 80.8 mmol), I-31 (56.9 g, 161.5mmol), cesium carbonate (52.6 g, 161.5 mmol) and Pd(PPh₃)₄ in 225 ml ofAr degassed DMA and 75 ml of water. This is equipped with a condenserunder argon and then heated to 140° C. on a preheated reaction block.After 45 min, the reaction is cooled to rt and then filtered. The solidsare rinsed with minimal EtOAc. The combined filtrates are transferred toa 2 L separatory funnel, diluted with approximately 750 mL of water andextracted with EtOAc (750 mL). The EtOAc is then rinsed with another 750mL of water and then 750 mL of brine. The organics are then combined,dried over sodium sulfate, filtered and concentrated in vacuo. Flashchromatography (SiO₂, 0-75% EtOAc/heptane) yields 25 g of I-101. Theimpure fractions are isolated and re-purified by flash chromatography(SiO₂, 0-75% EtOAc/heptane) to yield 7.5 g of I-101. Total 33 g of I-101(75%), m/z=560.4 [M+H].

The following intermediate is prepared in similar fashion:

Inter- me- Structure diate m/z

I-102 542.3/ 543.3 [M + H]

Method Q

Synthesis of Intermediate I-103

Hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) (79 mg, 0.19 mmol) is added toI-95 (1.0 g, 1.9 mmol) in water (3.0 mL) and ethanol (15 mL). Theheterogeneous reaction is heated to 80° C. After 18 h, the reaction iscooled to rt. The reaction is concentrated in vacuo. The residue iscombined with EtOAc and filtered. The filtrate is concentrated in vacuoto yield 500 mg of I-103, m/z=532.3 [M+H]. The product is used insubsequent steps without further purification.

The following intermediates are prepared in similar fashion:

Inter- Structure mediate m/z

I-104 560.4 [M + H]

I-105 546.4 [M + H]

I-106 614.4 [M + H]

I-107 614.4 [M + H]

I-108 560.4 [M + H]

I-109

I-110 492.3 [M + H]

I-111

I-112 506.4 [M + H]

I-113 542.3 [M + H]

I-114 560.2 [M + H]

I-115 594.3 [M + H]

I-116 594.3 [M + H]

I-117 574.3 [M + H]

I-118 574.4 [M + H]

I-119 574.4 [M + H]

I-120 594.3 [M + H]

I-121 638.3/640.3 [M + H]

I-122 578 [M + H]

I-123 578 [M + H]

I-124 578 [M + H]

I-125 578 [M + H]

I-126 574.2 [M + H]

I-127 592.2/594.4 [M + H]

I-128 588.3 [M + H]

I-129 520.4 [M + H]

Method R

Synthesis of Intermediate I-130

I-102 (61.5 g; 113.6 mmol) is dissolved in ethanol (200 mL) and water(40 mL).

Hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) (2.91 g; 6.8 mmol) is added andthe reaction allowed to stir at 80° C. for 16 h. The reaction solutionis diluted with water, extracted with 5% MeOH/CH₂Cl₂ and the organiclayer is collected, dried over MgSO₄, filtered and concentrated invacuo. The residue is purified by flash chromatography (SiO₂, 0-100%EtOAc in Hep then 0-20% MeOH in CH₂Cl₂) to yield 57.2 g of I-130,m/z=560.3 [M+H].

Method S

Synthesis of Intermediate I-131

Hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) (2.91 g; 6.8 mmol) (863 mg 2.0mmol) is added to the solution of I-101 (11.4 g, 20.2 mmol) in water (30mL) and ethanol (100 mL) in a sealable vessel. The vessel is sealed andheated to 95° C. overnight. The reaction is concentrated in vacuo,diluted with EtOAc and filtered through Celite. The filtrate isconcentrated in vacuo to yield 12 g of I-131, m/z=560.4 [M+H]. Thematerial (I-131) is used without further purification.

Method T

Synthesis of Intermediate I-132

I-109 (1.04 g, 2.5 mmol), I-41 (1.5 g, 5.0 mmol), cesium carbonate (1.64g, 5.0 mmol), Pd(PPh₃)₄ (0.29 g, 0.25 mmol), are combined in a microwavetube. Degassed dioxane (8 mL) and water (2 mL) are added. The reactionvessel is sealed under Ar and heated in a microwave for 60 min at 125°C. The reaction is transferred to a separatory funnel, diluted withEtOAc and rinsed with water and brine. The organics are dried, filtered,and concentrated in vacuo. The residue is then purified via flashchromatography (SiO₂, 0-20% MeOH in DCM) to yield 1000 mg of I-132,m/z=517.4 [M+H].

Method U

Synthesis of Intermediate I-133

I-95 (1.34 g, 2.6 mmol) is heated to 140° C. in trimethylorthoformate(R-12) (17.4 mL). After 18 h the excess trimethylorthoformate is removedin vacuo. The yellow residue is diluted with absolute ethanol (15 mL),sodium borohydride (R-13) (118 mg, 3.1 mmol) is added and the mixturestirred at rt. After 3 h, the solvent is removed in vacuo. The residueis diluted with water, extracted with EtOAc, dried over MgSO₄, filteredand concentrated in vacuo. The crude residue is purified by flashchromatography (SiO₂, 10-80% EtOAc in heptane) to yield 920 mg of I-133,m/z=528.3 [M+H].

The following intermediates are prepared in similar fashion:

Inter- Structure mediate m/z

I-134

I-135 556.5 [M + H]

Method V

Synthesis of Intermediate I-136

Hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) (70 mg, 0.16 mmol) is added toI-133 (890 mg, 1.7 mmol) in water (0.8 mL) and ethanol (2.4 mL). Theheterogeneous reaction is heated to 80° C. After 18 h, the reaction iscooled to rt. Additional hydrido(dimethylphosphinous acid-KP)[hydrogenbis(dimethylphosphinito-KP)]platinum(II) (80 mg, 0.19 mmol) is added andthe reaction is heated to 80° C. for 96 h. The reaction is concentratedin vacuo and partitioned between EtOAc and water. The layers areseparated and the aqueous layer is extracted with EtOAc (2×). Thecombined organic layers are washed with brine, dried over MgSO₄,filtered and concentrated to give a residue that is purified by flashchromatography (SiO₂, 30-100% EtOAc in heptane) yielding 500 mg ofI-136, m/z=546.4 [M+H].

The following intermediates are prepared in similar fashion:

Structure Intermediate m/z

I-137 478.7 [M + H]

I-138 560.3 [M + H]

I-139 526.2 [M + H]

I-140 576.4 [M + H]

I-141 510 [M + H]

I-142 510 [M + H]

I-143 526.2 [M + H]

I-144 576.4 [M + H]

I-145 544.2/546.2 [M + H]

I-146 544.2/546.2 [M + H]

I-147 544.2/546.1 [M + H]

I-148 528.3 [M + H]

I-149 590.4 [M + H]

I-150 578.2 [M + H]

I-151 578.3 [M + H]

I-152 574.3 [M + H]

I-153 556.3 [M + H]

I-154 546.4 [M + H]

I-155 538.3/540.3 [M + H]

I-156 574.2 [M + H]

I-157 540 [M + H]

Method W

Synthesis of Example 1

I-110 (84 mg, 0.17 mmol) is treated with a 4.0M HCl solution in dioxane(0.427 ml, 1.7 mmol) and stirred at rt for 0.5 h. The reaction isconcentrated in vacuo to afford 120 mg of I-158. To a solution ofacryloyl chloride (0.03 ml 0.37 mmol) in CH₂Cl₂ (5 mL) is added I-158and DIEA (0.15 mL, 0.84 mmol). After stirring at rt overnight, saturatedaqueous ammonium chloride (4 mL) is added and the mixture is extractedwith EtOAc (4×20 mL). The combined organic extracts are dried oversodium sulfate, filtered and concentrated in vacuo. The residue ispurified by RHPLC (Column: Luna PFP(2) Prep; Gradient: 25% to 30% ACN inWater (0.1% TFA)) to give 5 mg of Example 1.

The following compound is made in similar fashion: Example 26.

Method X

Synthesis of Example 2

To a solution of I-139 (220 mg, 0.42 mmol) in CH₂Cl₂ (5 mL) is added a4.0M HCl solution in dioxane (2.0 ml; 8.0 mmol) and the reaction isstirred at rt for 16 h. The solution is concentrated in vacuo to afford175 mg of I-159.

To a solution of 2-butynoic acid (35 mg; 0.41 mmol) in THF (5 ml) isadded isobutyl chloroformate (62 mg; 0.45 mmol) and N-methylmorpholine(166 mg; 1.6 mmol). The reaction is stirred at rt for 15 min then istransferred to a solution of I-159 (175 mg; 0.41 mmol) in THF (10 mL)and stirred for 1 h at rt. The mixture is then portioned between 10%MeOH in CH₂Cl₂ and water and filtered through a phase separator andfiltrate is concentrated. The residue is purified by flashchromatography (SiO₂, Ethyl acetate in heptane 0-100%, then MeOH inCH₂Cl₂ 0-20%) to yield, after concentrating in-vacuo, 127 mg of Example2.

The following compounds are made in similar fashion: Examples 3-9, 13,14, 19, 24, 27-29, 34-37,44, 52-60.

Method Y

Synthesis of Example 12

to a solution of I-130 (57 g, 102 mmol) in CH₂Cl₂ (250 mL) is added a4.0M HCl solution in dioxane (101.9 mL, 407.4 mmol). This reactionsolution is allowed to stir at over for 16 h then concentrated in vacuoto afford 57.5 g of I-160 that is used without further purification.

A solution of 2-butynoic acid (11.6 g, 138 mmol) in IPAc (228 mL) iscooled to 0° C. and isobutyl chloroformate (18 mL, 138 mmol) followed byN-methylmorpholine (50.5 mL, 460 mmol) are added sequentially dropwise.The solution is allowed to stir at 0° C. for 15 min then is transferredto a solution of I-160 (57 g, 115 mmol) in IPAc (200 mL). The reactionmixture is stirred for 1 h then diluted with 300 mL of water and warmedto 50° C. for 3 h, then stirred overnight at rt. The heterogeneousmixture is vacuum filtered and the solid is washed with water, collectedand dried to yield 39 g of Example 12. The filtrate is collected andlayers are separated. The IPAc layer is concentrated and the residuesuspended in EtOAc and heated until a homogeneous solution is observed.The solution is cooled to rt and the resulting precipitate is filtered,collected and dried to yield an additional 8.2 g of Example 12.

Method Z

Synthesis of Example 22

To a solution of I-131 (77.4 g, 138.3 mmol) in CH₂Cl₂ (250 mL) is addedMeOH (50 mL) followed by a 4M HCl solution in dioxane (138.3 mL, 553.3mmol). This reaction solution is allowed to stir at rt for 4 h and thenconcentrated in vacuo to yield 69.6 g of I-161 that is used withoutfurther purification.

A solution of 2-butynoic acid (14.3 g, 168.4 mmol) in IPAc (350 mL) iscooled to 0° C. and isobutyl chloroformate (25.4 g, 182.4 mmol) followedby N-methylmorpholine (57.3 g, 561 mmol) are added sequentiallydropwise. The solution is allowed to stir at 0° C. for 30 min then istransferred to a solution of I-161 (69.6 g, 140.3 mmol) in IPAc (350mL). The solution is warmed to rt and stirred for 1 h then diluted with800 ml of water and warmed to 50° C. for 45 minutes. The mixture is thencooled to rt and stirred for 30 min and then filtered. The solid iscollected and dried to yield 55 g of Example 22.

Method AA

Synthesis of Example 25

To a solution of I-139 (624 mg, 1.15 mmol) in CH₂Cl₂ (10 mL) is added asolution of HCl in dioxane (4M, 2.8 mL, 11.5 mmol) dropwise. Thesolution is decanted and the residue is dried in vacuo to yield 571 mgof I-162. The crude material (I-162) is used without furtherpurification. A solution of I-162 (571 mg, 1.51 mmol) in DMF (10 mL) andDIEA (0.60 mL, 3.4 mmol) is stirred for 15 minutes then 2-butynoic acid(97 mg, 1.51 mmol) and HATU (440 mg, 1.1 mmol) are added. After 30minutes, saturated aqueous NH₄Cl (50 mL) is added, and the mixture isextracted with EtOAc. The organic extract is washed with water andbrine, dried over sodium sulfate, filtered and concentrated in vacuo togive a crude residue that is purified by flash chromatography (SiO₂,0-10% MeOH in EtOAc) yielding 55 mg of Example 25.

The following compounds are made in similar fashion: Examples 15-18, 21,23, 30-33, 38, 39, 40, 41, 51.

Method AB

Synthesis of Example 43

To a solution of I-103 (1.2 g, 2.3 mmol) in CH₂Cl₂ (15 mL) is added aHCl solution in dioxane (4M, 5 mL, 20 mmol). The mixture is stirred atrt for 1 h then concentrated in vacuo and the residue is triturated withCH₂Cl₂. The solid is filtered, collected and dried to yield 1.09 g ofI-163 that is used without further purification.

To a solution of the acrylic acid (50 mg, 0.69 mmol) and HATU (264 mg,0.69 mmol) in DMA (2.5 mL) is added I-163 (250 mg, 0.53 mmol) and DIEA(0.47 mL, 2.7 mmol). After stirring at rt overnight, the reaction isconcentrated in vacuo to afford a residue that is purified by flashchromatography (SiO₂, 0-10% MeOH in CH₂Cl₂) giving 106 mg of Example 43.

The following compounds are made in similar fashion: Examples 20, 42,48.

Method AC

Synthesis of Example 45

To a solution of I-137 (100 mg, 0.21 mmol) in CH₂Cl₂ (5 mL) is added TFA(1.5 mL) and the mixture is stirred at rt overnight. The reaction isconcentrated in vacuo to yield I-164 that is used without furtherpurification.

To a solution of the 2-butynoic acid (20 mg, 0.24 mmol) and EDC (78 mg,0.41 mmol) in DMF (1 mL) is added DIEA (0.12 mL, 0.80 mmol). After 15min, I-164 (100 mg, 0.27 mmol) is added.

After stirring at rt overnight, the reaction is concentrated in vacuo.Purification by RHPLC (10˜90%: ACN/H₂O with 0.1% TFA) yielded 9 mg ofExample 45.

Method AD

Synthesis of Example 47

I-106 (87 mg, 0.159 mmol) is dissolved in 5 mL of CH₂Cl₂. TFA (1 mL) isadded and the mixture is stirred at room temperature for 1 hour. Thesolution is concentrated in vacuo and the residue is dissolved in MeOHand filtered through a 500 mg Agilent StratoSpheres SPE column (MPPL-HCO₃). The filtrate is concentrated in vacuo to yield I-165 that isused without further purification.

To a solution of the 2-butynoic acid (17 mg, 0.207 mmol) and HATU (79 mg0.21 mmol) in DMA (1 mL), is added I-165 (71 mg, 0.159 mmol) and DIEA(0.083 mL, 0.48 mmol). After stirring at rt overnight, saturated aqueousNH₄Cl (4 mL) is added and the mixture is extracted with EtOAc (4×20 mL).The combined organic extracts are dried over sodium sulfate, filteredand concentrated in vacuo to afford a residue that is purified by flashchromatography (SiO₂, 1-6% MeOH in CH₂Cl₂) to give 21 mg of Example 47.

The following compounds are made in similar fashion: Examples 46, 49,50.

Method AE

Synthesis of Example 48

In a vial is placed I-164 (100 mg, 0.27 mmol), acrylic acid (28 mg, 0.4mmol), TBTU (127 mg, 0.4 mmol) and triethylamine (40 mg, 0.4 mmol) in 1mL of DMF. After stirring at rt overnight, the solvent is removed invacuo to provide a residue that is purified by RHPLC (10-80%MeCN/water+0.1% TFA) to yield 20 mg of Example 48.

Method AF

Synthesis of Example 11

To a solution of I-132 (1.0 g, 1.94 mmol) in CH₂Cl₂ (5 mL) is added TFA(3 mL) dropwise. After 3 h at rt, the solvent is removed to provide aresidue that is dissolved in MeOH and passed through multiple 500 mgAgilent StratoSpheres SPE columns (MP PL-HCO₃). The cartridges arewashed with MeOH. The filtrate is concentrated in vacuo to provide 806mg of I-167 that is used without further purification.

To a solution of 2-butynoic acid (197 mg, 2.3 mmol) in EtOAc (10 mL) isadded isobutyl chloroformate (350 mg, 2.5 mmol) followed byN-methylmorpholine (0.79 g, 7.7 mmol). The mixture is stirred for 10 minthen is added to a solution of I-167 (806 mg, 1.9 mmol) in THF (10 mL)and stirred for 30 min at rt. The reaction is diluted with water andextracted with EtOAc, dried over MgSO₄, filtered, and concentrated. Thecrude residue is purified by flash chromatography (SiO₂, 0-10% MeOH inCH₂Cl₂) to yield 370 mg of Example 11.

The following compounds are made in similar fashion: Example 10

Therapeutic Use

On the basis of their biological properties the compounds of formula (I)according to the invention, or their tautomers, racemates, enantiomers,diastereomers, mixtures thereof and the salts of all the above-mentionedforms are suitable for treating autoimmune and allergic disorders inthat they exhibit good inhibitory effect upon BTK.

Such diseases include for example: rheumatoid arthritis, systemic lupuserythromatosis, lupus nephritis, Sjorgen's disease, vasculitis,scleroderma, asthma, allergic rhinitis, allergic eczema, B celllymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenileidiopathic arthritis, inflammatory bowel disease, graft versus hostdisease, psoriatic arthritis, ankylosing spondylitis and uveitis.

The compounds of formula (I) may be used on their own or in combinationwith at least one other active substance according to the invention,and/or optionally also in combination with at least one otherpharmacologically active substance. The other pharmacologically activesubstance may be an immunomodulatory agent, anti-inflammatory agent, ora chemotherapeutic agent. Examples of such agents include but are notlimited to cyclophosphamide, mycophenolate (MMF), hydroxychloroquine,glucocorticoids, corticosteroids, immunosuppressants, NSAIDs,non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, tumournecrosis factor receptor (TNF) receptors antagonists and methotrexate.

Suitable preparations include for example tablets, capsules,suppositories, solutions—particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may of course contain, apart from theabove-mentioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from I-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

Description of Biological Properties

BTK v. EGFR Inhibition Assay

BTK Lanthscreen® Eu Kinase Binding Assay:

A Lanthscreen® Eu Kinase Binding assay (Life Technologies) is performedto quantitate the ability of test compounds to bind to BTK. The assay isbased on the binding and displacement of Alexa Fluor647-labeled KinaseTracer #236 to the ATP-binding site of human full length His-tagged BTK(Life Technologies cat # PV3587) with TR-FRET detection using aeuropium-labeled anti-His antibody. The assay is assembled in 384-welllow volume NBS black plates (Corning) where 2 nM BTK and test compoundin DMSO at varying concentrations are pre-incubated for 30 min at 28° C.in assay buffer consisting of 50 mM HEPES, pH 7.4, 10 mM MgCl₂, 1 mMEGTA. 100 μM Na₃VO₄ and 0.01% Brij 35. Then, 2 nM of Eu-anti Hisantibody and 30 nM Kinase Tracer are added and incubated for 60 min at28° C. Following incubation, TR-FRET signal is read on an Envision platereader (Excitation: 340 nm; Emissions: 615 and 665 nm). The 665:615 nmemission ratio is calculated and converted to POC compared to controland blank wells.

Inhibition of IL-6 Production in B Cells Co-Stimulated with ODN 2006 andAnti-hIgD

Primary CD19+ B cells (AllCells # PB010F) are thawed and plated in RPMIcontaining 10% HI FBS in a 384-well tissue cultured plate at 20,000cells/well. The cells are treated with test compound (0.5% DMSO finalconcentration) and incubated for 1 hour at 37° C., 5% CO2. Cells arethen stimulated with 5 ug/mL Goat F(ab′)2 anti-human IgD(SouthernBiotech #2032) and 2 uM ODN 2006 (InvivoGen # tlrl-2006) andincubated for 18-24 hours at 37° C., 5% CO₂. IL-6 in the supernatant ismeasured using Meso Scale Discovery kit # K211AKB-6.

Inhibition of EGFR Autophosphorylation in A431 Human Epithelial CellsStimulated with Epithelial Growth Factor

A431cells (ATCC # CRL-1555 FZ) are thawed and plated in DMEM containing10% FBS in a 384-well tissue culture treated plate at 15,000 cells/well.After incubating for 24 hours at 37° C., 5% CO₂, the cells are treatedwith test compound (1% DMSO final concentration) and incubated for 16hours at 37° C., 5% CO₂. EGF (Millipore, 01-107) is added at a finalconcentration of 60 ng/mL and incubated for 10 minutes. The medium isremoved, the cells are lysed, and phospho EGFR is measured (Meso ScaleDiagnostics, N31CB-1).

Representative compounds of the present invention are tested and showBTK inhibition (Table I). Thus, they have the ability to demonstrateclinical benefit for the treatment of autoimmune disorders.Additionally, compounds of the present invention, as represented byexamples in Table II, are selective for BTK inhibition over otherrelated kinases. For example, the data presented in Table IIdemonstrates that the compounds of the present invention possess highdegree of BTK selectivity over EGFR. In this table the BTK activity ismeasured by IL-6 production in primary CD19⁺ B cells, and the EGFRactivity is measured by EGFR phosphorylation in A431 cells.

TABLE II EGFR selectivity data for representative compounds of thepresent invention Example B-cell IL-6 IC₅₀ (nM) A431 p-EGFR IC₅₀ (nM) 20.3 >10000 3 1.2 >10000 6 1.0 >10000 7 72 >10000 8 2.5 >10000 101.1 >10000 12 0.5 >10000 14 1.1 >10000 16 2.0 >10000 18 8.0 >10000 192.3 >10000 21 9.2 >10000 22 0.8 >10000 23 4.5 >10000 25 6.1 >10000 264.0 >10000 27 3.4 >10000 30 2.4 >10000 32 1.3 >10000 33 1.2 >10000 360.5 >10000 44 0.7 >10000 47 1.1 >10000 51 1.9 >10000 52 0.5 >10000 530.4 >10000 54 0.4 >10000 55 1.5 >10000 56 0.7 >10000 58 3.4 >10000 590.4 >10000 60 0.6 >10000

Therefore, as can be appreciated by a person skilled in the art, thecompounds of the present invention have a lower potential for adverseeffects due to off-target activity, as demonstrated by their highselectivity against EGFR in cellular assays.

BTK v. BMX, TEC and TXK Inhibition Assays

Preferred compounds of the present invention display a range ofselective inhibition of BTK over other related kinases BMX, TEC, and TXKrelative to known BTK inhibitors. The following are used as testcompounds: compounds of the present invention and1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one(comparative compound A, ibrutinib),5-amino-1-(7-but-2-ynoyl-7-azaspiro[3.4]octan-2-yl)-3-(4-isopropoxyphenyl)pyrazole-4-carboxamide (comparative compound B, Example 168WO2014/025976),N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (comparative compound C, Journal of Pharmacology andExperimental Therapeutics 2013, 346:219-228) which are known BTKinhibitors.

BTK, BMX, and TXK Assays

Z′-LYTE™ Assay (Life Technologies):

The Z′-Lyte assay employs a FRET-based, coupled-enzyme format and isbased on the differential sensitivity of phosphorylated andnon-phosphorylated peptides to proteolytic Cleavage. The activity ofhuman recombinant BTK (full length, His-tagged), BMX (full length,His-tagged) or Txk (full length, GST-tagged) is estimated by measuringthe phosphorylation of a synthetic FRET peptide substrate labeled withCoumarin and Fluorescein. The 10 μL assay mixtures contain 50 mM HEPES(pH 7.5), 0.01% Brij-35, 10 mM MgCl2, 1 mM EGTA, 2 μM FRET peptidesubstrate (Z′-LYTE™ Tyr 1 Peptide for BTK and BMX, and Tyr 06 peptidefor TXK), and kinase (1.3-9.3 ng BTK; 2.8-45.0 ng BMX; 2.3-93.6 ng TXK).Incubations are carried out at 22° C. in black polypropylene 384-wellplates (Corning). Prior to the assay, kinase, FRET peptide substrate andserially diluted test compounds are pre-incubated together in assaybuffer (7.5 μL) for 10 min, and the assay is initiated by the additionof 2.5 μL assay buffer containing 4×ATP (25 μM for BTK; 100 μM for bothBMX and TXK). Following the 60 min incubation, the assay mixtures arequenched by the addition of 5 μL of Z′-LYTE™ development reagent, and 1hour later the emissions of Coumarin (445 nm) and Fluorescein (520 nm)are determined after excitation at 400 nm using an Envision platereader. An emission ratio (445 nm/520 nm) is determined to quantify thedegree of substrate phosphorylation.

TEC Assay

Lanthscreen® Eu Kinase Binding Assay (Life Technologies):

Lanthscreen® Eu Kinase Binding assay for BMX is performed as describedabove for BTK except that 1 nM human recombinant full length TEC(His-tagged) kinase and 1 nM Alexa Fluor647-labeled Kinase Tracer #178were used instead.

Representative compounds of the present invention are assessed forinhibition of BTK, BMX, and TXK measuring phosphorylation of a substrate(Z′-LYTE™ assay, Life Technologies) and TEC measuring displacement of a“tracer” (Lanthscreen® Eu Kinase Binding assay, Life Technologies).

TABLE III BMX, TEC and TXK selectivity for compounds of the presentinvention BTK IC₅₀ BMX IC₅₀ TEC IC₅₀ TXK IC₅₀ Example (nM) (nM) (nM)(nM) Compound A 1.4 0.8 12 2.3 Compound B 0.9 2.2 44 2.3 Compound C 6.13.2 6.8 22 2 0.8 16 14 25 3 1.2 17 45 27 6 1.5 33 65 43 7 29 870 1200630 8 4.4 85 130 120 10 1.4 50 120 100 11 1.8 37 73 150 12 1.7 21 92 13014 1.7 150 92 180 16 13 160 220 430 18 3.1 120 110 270 19 5.0 290 160220 21 40 3000 1100 1900 22 0.7 29 21 46 23 8.3 280 130 600 25 19 300160 850 26 18 1200 430 3000 27 6.6 120 66 120 28 1.2 56 39 95 29 3.6 7879 92 30 3.0 120 64 160 32 1.9 64 49 55 33 1.3 25 48 59 36 1.0 37 22 5044 1.4 24 20 78 47 2.7 500 34 310 51 0.8 8.0 18 12 52 7.0 160 100 260 531.3 34 47 84 54 1.5 27 35 110 55 2.5 35 67 79 56 2.2 54 120 150 58 2.646 38 67 59 0.8 38 36 68 60 1.7 27 35 100

These results show that the compounds of the present invention areselective for BTK inhibition as compared to other kinases by at leastabout 10 folds. See Table III

In-Vivo Assay—Comparison Between the Compounds of the Present Inventionand Comparative Compounds A, B and C

In a side-by-side in-vivo study, select compounds of the presentinvention and comparative compounds A-C are evaluated intelemetry-instrumented conscious rats to determine their effects on meanarterial pressure (MAP) at doses at or above therapeutically relevantconcentrations. The following compounds are evaluated at 10 mg/kg po qdand 30 mg/kg po qd over the course of five days: Examples 12 and 22 ofthe present invention and comparative compounds A-C, i.e.,1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one(comparative compound A, ibrutinib),5-amino-1-(7-but-2-ynoyl-7-azaspiro[3.4]octan-2-yl)-3-(4-isopropoxyphenyl)pyrazole-4-carboxamide (comparative compound B, Example 168WO2014/025976) andN-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (comparative compound C, Journal of Pharmacology andExperimental Therapeutics 2013, 346:219-228).

Experimental Protocol

All animals (telemetry-instrumented) are single housed in metaboliccages. Rats are acclimated to the metabolic cage for at least 3 days andthen dosed with vehicle for up to 4 days. Blood pressure, heart rate,and bodyweight are collected during the baseline period and animals arerandomized into 3 groups based on these parameters (n=8-9/group).Treatment groups are: vehicle and test compound (10 mg/kg po and 30mg/kg po qd); animals are treated with compound for 5 days. Thefollowing day, rats are dosed again with the test compound and plasmasamples are collected via tail bleed for compound exposures at multipletimepoints post-dose to capture the T_(max) (n=3-9/group). Mean arterialpressure (MAP) and heart rate (HR) are collected continuously throughoutthe study. Statistical analyses is performed using GraphPad Prism basedon the average 24-hr mean value during five days of compoundadministration (one-way ANOVA with Dunnett's post-test vs. Vehicle;p<0.05 is considered statistically significant).

TABLE IV 5-Day 24-h MAP Dose C_(max) (nM) (mmHg) Change Example (mg/kg)Day 6 versus Control Example 12 10 111 ± 37  No statisticallysignificant effect on MAP Example 12 30 344 ± 106 No statisticallysignificant effect on MAP Compound A 10 319 ± 36  3 ± 1 mmHg Compound A30 561 ± 183 4 ± 1 mmHg Compound B 10 182 ± 17  3 ± 1 mmHg Compound B 30480 ± 53  2 ± 1 mmHg Compound C 10 644 ± 96  4 ± 1 mmHg Compound C 301731 ± 434  5 ± 1 mmHg Example 22 10 170 ± 29  No statisticallysignificant effect on MAP Example 22 30 720 ± 262 No statisticallysignificant effect on MAP

The results show that the compounds of the present invention, e.g.,Examples 12 and 22, elicit no effect on MAP in rats as compared to thecomparative compounds A, B and C. As can be appreciated by a personskilled in the art, significant changes in the mean arterial pressure inrats could be indicative of higher risk of adverse cardiovascular eventsin a clinical setting. Therefore, the fact that the compounds of thepresent invention do not display statistically significant effects onMAP is surprising and unexpected. See Table IV and FIG. 1.

All patent and non-patent documents or literature cited in thisapplication are herein incorporated by reference in their entirety.

1-23. (canceled)
 24. A compound of the formula (I)

wherein: Cy is chosen from

each R₁ is independently chosen from hydrogen or methyl; R₂ is L-Ar,wherein Ar is phenyl or pyridinyl and each is optionally substituted byone or more of halogen, halo C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CN,halo C₁₋₄ alkoxy, or cycloalkyl; L is —(CH₂)— or —(CHCH₃)—; Y is C₆-C₈spirocycle containing 1 ring nitrogen atom, and is substituted by oneR₃; R₃ is chosen from

and each R₄ is independently chosen from hydrogen, C₁₋₄ alkyl, or C₃₋₄cycloalkyl; each group defined above for R₁-R₄ and Y can be wherepossible partially or fully halogenated; or a pharmaceuticallyacceptable salt thereof.
 25. The compound according to claim 24, whereinY is chosen from

or a pharmaceutically acceptable salt thereof.
 26. The compoundaccording to claim 24, wherein Cy is

or a pharmaceutically acceptable salt thereof.
 27. The compoundaccording to claim 24 and wherein Cy is

or a pharmaceutically acceptable salt thereof.
 28. The compoundaccording to claim 24 chosen from:

or a pharmaceutically acceptable salt thereof.
 29. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 30. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 31. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 32. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 33. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 34. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 35. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 36. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 37. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 38. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 39. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 40. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 41. The compoundaccording to claim 28 of the formula:

or a pharmaceutically acceptable salt thereof.
 42. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 24 or a pharmaceutically acceptable salt thereof. 43.A method of treating a disease chosen from rheumatoid arthritis,systemic lupus erythromatosis, lupus nephritis, Sjogren's disease,vasculitis, scleroderma, asthma, allergic rhinitis, allergic eczema, Bcell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis,juvenile idiopathic arthritis, inflammatory bowel disease, graft versushost disease, psoriatic arthritis, ankylosing spondylitis and uveitis,comprising administering to a patient a therapeutically effective amountof a compound according to claim 24 or a pharmaceutically acceptablesalt thereof.